This invention relates to a method of use of a composition of matter. More particularly, the invention relates to a novel method of using a pharmaceutical composition comprising erythropoietin for treating ischemic acute renal failure (ARF) and for preventing the onset of ischemic ARF.
Clinical acute renal failure (ARF) remains a common and serious complication associated with high morbidity and mortality. Moderately effective measures to prevent ARF include volume expansion, and in renal transplants, mannitol administration. The uremic state, volume and electrolyte disturbances can be readily corrected by hemodialysis, and outcomes are improved when more biocompatible dialysis membranes are used. In addition, administration of atrial natriuretic peptide has been found to speed the improvement of renal function in some patients with ARF.
In the induction phase of ARF, cell necrosis, apoptosis, and sub-lethal injury are observed [1,2,3,4,5,6]. These effects are thought to collectively contribute to the loss of renal function via pathological activation of tubuloglomerular feedback, back leak of ultrafiltrate, tubular obstruction and ineffective transport by partially depolarized tubular cells [1,2,3,4,5,6]. In the repair phase of ARF, reepithelialization of injured tubules is accomplished by migration of cells (xe2x80x9cmotogenesisxe2x80x9d) into deepithelialized nephron segments, cell proliferation (xe2x80x9cmitogenesisxe2x80x9d), and redifferentiation of newly generated and sublethally injured tubular cells [1,6,7]. Anabolic mechanisms and improvement of intrarenal hemodynamics are also critical to functional recovery [1,2,8,9,10].
A number of growth factors, including IGF-I, EGF and HGF, and atrial natriuretic peptide have been shown to improve renal outcome in animals with experimental ARF by modulation of the cellular and hemodynamic responses that are characteristic in ARF [8,9,10]. However, neither IGF-I nor atrial natriuretic peptide has been found to improve outcomes in patients with ARF [11,12]. Thus, successful treatment of experimental ARF in animal models is not indicative of success in humans.
EPO controls erythropoiesis by receptor-mediated regulation of survival, proliferation, and differentiation of erythroid progenitor cells [13,14]. In adult mammals, erythropoietin (EPO) is primarily produced by type-I interstitial cells of the juxtamedullary renal cortical labyrinth [13,14,15,16,17]. Renal and hepatic EPO synthesis and release are increased when intrarenal or hepatic tissue oxygenation is decreased. Renal EPO secretion occurs first into peritubular capillary blood that contains residual EPO and that reaches a large number of renal cells before delivering the hormone, via renal veins, into the systemic circulation. Intriguingly, EPO-producing cells are also in direct contact with basal aspects of proximal and distal tubular cells [15,16,17,18,19,20]. The anatomical relationships that exist between EPO secreting cells, the intrarenal capillary network, and the tubular and other renal cells, may serve therefore to facilitate endocrine and paracrine actions of EPO within the kidney itself. It has recently been reported that authentic, mitogenically active EPO receptors (EPORs) are present in both proximal and distal renal tubular cells [21]. Since these tubular cells express EPORs, endocrine actions can be elicited.
As described previously, specific EPOR mRNAs have been shown to be expressed in the cortex, medulla and papilla of both human and rat kidneys, and EPOR protein has been identified in mouse and human proximal tubular cells [21]. Activation of EPORs in mouse proximal tubular cells by EPO was shown to stimulate DNA synthesis and cell proliferation in vitro, but the specific effect of EPO has not been described in vivo.
EPO has been described in the past as an effective treatment for cis-platinum induced ARF in rats. This form of ARF was induced by the administration of cis-platinum, a chemotherapeutic agent, and while it shows that EPO has an effect on recovery of kidney function, it does not address the more common and more serious clinical form of ARF caused by ischemia. The study also did not describe the underlying cellular and molecular effects of EPO on the renal tubular cells and provided no information regarding the expression of EPORs in renal cells [22]. In another study, EPO was administered intravenously in suprapharmacologic doses (500 to 3000 U/kg body weight) and improved hematocrits of rats with uninephrectomy and contralateral ischemic ARF, but had no effect on renal function, it increased, however animal survival by an unknown mechanism [23].
The use of EPO has also been disclosed in the past as a method to reduce excessive bleeding in patients in need thereof, such as an individual with a gunshot wound. U.S. Pat. No. 6,274,158 describes the administration of EPO in order to thicken the blood. Blood thickens as a result of EPO""s effect of increasing production of red blood cells. At the high dosage levels necessary to produce the blood-thickening effect, EPO""s helpful renoprotective functions are not produced.
Due to the high mortality and morbidity among individuals with ischemic ARF, a novel treatment strategy for both protecting against the onset of ischemic ARF and for treating individuals suffering from ischemic ARF would be a significant advancement in the art.
The present invention provides a method of preventing the onset of ischemic ARF in an individual by administration of a composition of EPO in a pharmaceutically acceptable carrier.
The present invention also provides a method for treating an individual suffering from ischemic ARF by administration of a composition of EPO in a pharmaceutically acceptable carrier.
The present invention also provides a method for preventing potentially harmful cell apoptosis in renal tubular cells by administration of a composition of EPO in a pharmaceutically acceptable carrier.
The present invention also provides a method for stimulating motogenesis and mitogenesis in renal tubular cells by administration of a composition of EPO in a pharmaceutically acceptable carrier.
Preferably, the EPO is recombinant or naturally-derived EPO, and the composition is administered systemically such that the EPO circulates through the body. The composition can further comprise other ingredients such as pharmaceutically acceptable solvents, diluents, excipients, emulsifiers, stabilizers, and mixtures thereof.